Date of Award
Doctor of Philosophy (PhD)
J. Matthew Mahoney
There is a well-established relationship between epilepsy and genetics. A range of genetic architectures exists, from monogenic disorders with a single causal gene mutation to polygenic forms caused by multiple common interacting variants and their aggregated effects. As a result of this genetic complexity, the epilepsies exhibit extreme phenotypic heterogeneity, with multiple seizure types and comorbidities varying in presence and severity across patients. Indeed, nominally monogenic forms of epilepsy can have vastly different clinical manifestations even among individuals with the same gene mutation. Alternatively, many gene mutations can result in the same electrographic seizure type. Thus, the map from genotype to phenotype is both one-to-many and many-to-one. In model systems, we can systematically probe the genotype-phenotype map to gauge both primary effects of epilepsy-causing mutations and modifier effects that arise from interactions with the rest of the genome.In this dissertation, I study two distinct, but archetypal, classes of genetic epilepsy: tuberous sclerosis complex (TSC) and genetic generalized epilepsies (GGE). TSC is an autosomal dominant disorder caused by well-characterized mutations, while GGE is a heritable syndrome for which there is no singular cause, although there are monogenic forms. By investigating monogenic insults in mice and the resulting phenotypic heterogeneity as a function of genetic background diversity, I uncover genetic modifiers of these disorders responsible for mitigating or aggravating the effects of the original insult. In our first study, I developed a novel mouse model of TSC, which is caused by loss-of-function mutations in the TSC1 or TSC2 genes. Human patients are always heterozygous for such a mutation and can present with severe epilepsy, brain lesions, and neuropsychiatric disorders. However, current TSC mouse models are not reflective of human TSC, either because they do not accurately model the gene dosage or the phenotypic effects. By systematically modifying the genetic background of heterozygous Tsc1 knockout mice, I show for the first time that chronic epilepsy can occur in a heterozygous mouse, making our model the first construct-valid and face-valid model of TSC-associated epilepsy. Importantly, I did not observe epilepsy across all genetic backgrounds, demonstrating that phenotypic differences among mice with the same Tsc1 gene mutation were the result of genetic modifiers, which can potentially be mapped and exploited as therapeutic targets. In a second study, I performed a computational analysis of genetic modifiers of GGE. Absence seizures are common in GGEs and are characterized by brief lapses in awareness and spike-and-wave discharges (SWD) seen on EEG. In a prior mapping study by our collaborators, a series of crosses between transgenic seizure-resistant and seizure-prone strains, each carrying a distinct SWD-causing mutation, demonstrated an antagonistic epistatic interaction between two modifier loci, independent of the causal mutation. Thus, their study implicated universal modifiers in the background acting through common pathways. To address low mapping resolution of these loci, I used a genetic network analysis to integrate their results with human GGE risk genes to prioritize candidate genes as modifiers. Our top-ranking genes implicate neurodevelopmental regulators and cytoskeletal organization as key modifier pathways influencing GGE severity. Across these two projects, I saw a similar theme: genetic diversity is a critical tool to dissect the phenotypic heterogeneity of the epilepsies.
Number of Pages
Lara, Montana Kay, "Genetic Diversity and Background Modifiers of Complex Seizure Disorders" (2023). Graduate College Dissertations and Theses. 1692.
Available for download on Sunday, April 20, 2025